Chemoenzymatic Synthesis of a Rhamnose-Functionalized Bispecific Nanobody as a Bispecific Antibody Mimic for Cancer Immunotherapy

Angew Chem Int Ed Engl. 2022 Sep 19;61(38):e202208773. doi: 10.1002/anie.202208773. Epub 2022 Aug 17.

Abstract

Bispecific antibodies (BsAbs) are next-generation therapeutics for complex cancer treatment. Herein, we developed a dual-targeting non-IgG format of bsAbs by using a bispecific nanobody (bsNb) that can simultaneously target EGFR and HER2 on tumor cells. Site-specific modification of the anti-EGFR-HER2 bsNb was conducted using the rhamnose (Rha) hapten via sortase A-mediated ligation to reconstitute the missing crystallizable fragment (Fc) effector biological functions. Functionally similar to bsAbs, bsNb-Rha conjugates retained dual-targeting activity and exerted potent anticancer effects via the Fc-domain-mediated engagement of endogenous anti-Rha antibodies. Further, an optimized bsNb-Rha conjugate exhibited markedly improved pharmacokinetics and efficient inhibitory effects against xenograft tumor growth in vivo. Our strategy provides a general and cost-effective platform to generate a new bsAb format for cancer immunotherapy.

Keywords: Bispecific Nanobodies; Cancer Immunotherapy; Fc Biological Functions; Rhamnose; Sortase A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Bispecific* / pharmacology
  • Antibodies, Bispecific* / therapeutic use
  • Humans
  • Immunotherapy
  • Neoplasms* / drug therapy
  • Rhamnose

Substances

  • Antibodies, Bispecific
  • Rhamnose